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A perforated-patch whole-cell recording method was used to determine whether nitric oxide signaling participates in acetylcholine (ACh)-induced regulation of basal L-type Ca2+ current (ICa,L) in cat atrial myocytes. Exposure to 1 µM ACh for 2 min inhibited basal ICa,L (–21 ± 3%), and withdrawal of ACh elicited rebound stimulation of ICa,L above control (80 ± 13%) (n = 23). Stimulation of ICa,L elicited by withdrawal of ACh (but not ACh-induced inhibition of ICa,L) was blocked by either 50 µM hemoglobin; 30 µM ODQ or 10 µM methylene blue, inhibitors of soluble guanylate cyclase; 10 µM W-7, a calmodulin inhibitor; or 10 µM L-NIO, an inhibitor of constitutive NO synthase (NOS). In cells incubated in 5 mM l-arginine, ACh-induced rebound stimulation of ICa,L was enhanced compared with control responses. Histochemical assay (NADPH diaphorase) indicated that atrial myocytes express constitutive NOS. NO-donor, spermine/NO (SP/NO), >1 µM stimulated basal ICa,L. SP/NO-induced stimulation of ICa,L was inhibited by 50 µM hemoglobin, 30 µM ODQ, or 5 µM H-89, an inhibitor of PKA, and was unchanged by 50 µM MnTBAP, a peroxynitrite scavenger. When ICa,L was prestimulated by 10 µM milrinone, an inhibitor of cGMP-inhibited phosphodiesterase (type III) activity, SP/NO failed to further increase ICa,L. In cells incubated in pertussis toxin (3.4 µg/ml for 6 h; 36°C), ACh failed to affect ICa,L, but 100 µM SP/NO or 10 µM milrinone still increased basal ICa,L. These results indicate that in cat atrial myocytes NO signaling mediates stimulation of ICa,L elicited by withdrawal of ACh but not ACh-induced inhibition of basal ICa,L. NO activates cGMP-induced inhibition of phosphodiesterase (type III) activity. Upon withdrawal of ACh, this mechanism allows cAMP to recover to levels above control, thereby stimulating ICa,L. Pertussis toxin–sensitive G-proteins couple M2 muscarinic receptors to NO signaling. NO-mediated stimulation of ICa,L elicited by withdrawal of ACh may be an important mechanism that rapidly restores cardiac pacemaker and contractile functions after cholinergic suppression of atrial activity.
Key Words: electrophysiology • cyclic AMP • cyclic GMP • calmodulin • phosphodiesterase
Ms. Rechenmacher died on 17 August 1997.
Address correspondence to Stephen L. Lipsius, Ph.D., Department of Physiology, Loyola University Medical Center, 2160 S. First Avenue, Maywood, IL 60153. Fax: 708-216-6308; E-mail: slipsiu{at}wpo.it.luc.edu
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